Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction
Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction
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DOI：
10.1073/pnas.0504438102
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发表时间：
2005-08-09
影响因子：
11.1
通讯作者：
Sanna, PP
中科院分区：
文献类型：
--
作者：
Ahmed, SH;Lutjens, R;Sanna, PP
通过使用高密度寡核苷酸阵列，我们分析了大鼠奖励相关大脑区域的基因表达，这些大鼠在延长可卡因摄入量（每天 6 小时）后可卡因摄入量不断增加。大鼠每天限制摄入可卡因（仅 1 小时），显示出稳定的可卡因摄入水平，而未接触过可卡因的大鼠则用作对照。比较了四种分析方法：Affymetrix MICROARRAY SUITE 4 和 MICROARRAY SUITE 5（使用完美匹配减失配模型）以及 DCHIP 和 RMA（使用仅完美匹配模型来生成表达值）。通过独立重复实验，在个体动物中通过 RT-PCR 验证了结果。少数基因与可卡因摄入量增加有关（ESC 基因）。出乎意料的是，在检查的大脑区域[前额皮质、伏隔核、隔膜、下丘脑外侧（LH）、杏仁核和腹侧被盖区]中，LH 对可卡因摄入量的增加具有最强的转录反应。大多数已鉴定的 ESC 基因也在突触发生和突触可塑性过程中表达，包括编码参与神经传递的几种突触前和突触后蛋白质的基因。这些结果表明，在可卡因使用量增加期间，LH 内在电路经历了结构重组。 LH 回路的这种重塑可能会导致奖赏功能的慢性缺陷，人们推测这种缺陷会导致药物成瘾的转变。结果还支持使用多种分析策略来识别基因表达中最稳健的变化并补偿影响每种策略的偏差的价值。
By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix MICROARRAY SUITE 4 and MICROARRAY SUITE 5, Which use perfect-match-minus-mismatch models, and DCHIP and RMA, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy.